There are at present several commercially available inhalation preparations useful for the treatment of asthma, bronchial spasm, and reversible bronchoconstriction. These preparations are either certain catacholamines in powder form or solution, or a solution of the adrenal cortical steroid, dexamethasone. For administration, the powder is sprayed or the solution is first atomized and then sprayed directly into the nasal or oral opening. In addition, there is an inhalable powder comprising a bis-chromone derivative; however, this medicament has no intrinsic bronchodilator, or anti-histamine activity, and is useful only prophylactically. It is not indicated for treating an acute asthmatic attack. The literature also describes the use of certain prostaglandins by the oral inhalation route for the relief of bronchial spasm. Thus, for example, Belgian Pat. No. 792,216 describes this use for prostaglandin F.sub.2.beta.. The use of certain quaternary salts of atropine as inhalable anticholinergic bronchodilators has been reported; Arzneium.-Forsch. (Drug Res.) 26, 959-1020 (1976). The use of certain quaternized phenothiazines [e.g. 1-(10-phenothiazinylmethyl)ethyl-2-hydroxyethyldimethylammonium chloride, Acta. Pharmacol. et Toxicol., 18, 105 (1961)] as antihistiminics (i.m. administration) has also been studied.
The existing inhalable medicaments useful for the control of asthma, bronchial spasm and similar disorders each, unfortunately, possess deleterious side effects, and a generally useful medicament, indicated for use by all patients requiring inhalation therapy, does not exist.
The catacholamines most often utilized are epinephrine, isoproterenol, and metaproterenol. These adrenergic agents are most powerful and useful drugs in the relief of severe asthmatic spasm (status asthmaticus); however, as with other dilators they have untoward side effects. Some of the more undesirable of these are stimulation of the cardiovascular and central nervous system, hyperglycemia, and tolerance (tachyphylaxis), which greatly reduces the effectiveness of these drugs.
Many cases of asthma and status asthmaticus refractory to usual treatment methods may now be controlled by the use of inhalable dexamethasone. However, long term treatment of asthma with steroids involves the risk of sodium retention, hypertension, ulcers, calcium loss from osseous structures, and other well-known side effects.
Thus, the agents presently available to the physician have a number of problems associated with their use, including toxicity, adverse effect on the cardiovascular system (especially in the sympathomimetics), and fluid retention or edema (with the corticosteroids). Thus, a definite need exists for means employing effective and well-tolerated bronchodilating agents.
The difficulty in finding such agents is well-known to those skilled in the art. It is a matter of common knowledge and experience, for example, that many compounds that relax smooth muscles are not bronchodilators by all common routes of administration (and especially by the aerosol route of administration). For example, for some obscure reason, ephedrine is a smooth muscle relaxant and is an orally active bronchodilator, but not by aerosol; epinephrine, also a smooth muscle relaxant, is used by aerosol but not orally. And aminophylline, a drug which can relax bronchial smooth muscle in vitro or by injection in vivo is inactive as a bronchodilator aerosol. In view of this it is suprising to find new means which, even though characterized by smooth muscle relaxing activity, provide bronchodilation by administration via the aerosol route, possess high levels of activity, and are non-toxic.
The present invention provides new, potent, bronchodilator compositions comprising quaternary salts of the well-known medicament, promethazine, which compositions are useful upon administration by the aerosol route.